Abstract
Several chemically diverse pruritogens, including bombesin, compound 48/80, norbinaltorphimine, and 5′-GNTI, cause rodents to scratch excessively in a stable, uniform manner and consequently provide convenient animal models of itch against which potential antipruritics may be evaluated, structure–activity relationships established, and the nature of spontaneous, repetitive behavior itself analyzed. Decreasing the number of scratching bouts in these apparently simple models has been the requisite first step in the progress of kappa opioid agonists such as nalbuphine, asimadoline, and CR845 toward clinical testing as antipruritics. Nalfurafine is the prime example of a kappa agonist spanning the developmental divide between scratching mice models and commercialization within 10 years. Patients undergoing hemodialysis and suffering from the itching associated with uremic pruritus, and potentially those inflicted with atopic dermatitis, are the beneficiaries.
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Abbreviations
- A50 (antiscratch-50):
-
The dose of test compound that antagonizes pruritogen-induced scratching by 50 % on a scale that ranges from vehicle (control) value to 100 %
- ACTH:
-
Adrenocorticotropic hormone
- ADL 10–0101:
-
N-Methyl-N-[(1S)-(1-phenyl-2-pyrrolidinyl)ethyl]-2-methane-sulfonamidylphenylacetamide methanesulfonate
- EKC:
-
Ethylketocyclazocine
- GR 94839:
-
4-Acetyl-1-(3,4-dichlorophenyl)acetyl-2-[(3-hydroxy-1-pyrrolidinyl)methyl]piperazine
- GRP:
-
Gastrin-releasing peptide
- ICI 204,448:
-
(RS)-[3-[1-[[3,4-Dichlorophenyl)acetyl]methylamino]-2-(1-pyrrolidinyl)ethyl]phenoxy]acetic acid
- icv:
-
Intracerebroventricular
- JDTic:
-
(3R)-7-Hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide
- JNJ 10191584:
-
1-[(5-Chloro-1H-benzimidazol-2-yl)carbonyl]-4-methylpiperazine
- JNJ 39758979:
-
(R)-4-(3-Amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine
- KOP:
-
Kappa opioid
- McN-A-343:
-
4-(m-Chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride
- norBNI:
-
Norbinaltorphimine
- ODT8-SS:
-
des-AA1,2,4,5,12,13[D-Trp8]somatostatin
- RC-3095:
-
[D-Tpi6 Leu13ψ(CH2NH)Leu14]bombesin (6–14)
- U-50,488:
-
trans-(±)-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide
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Acknowledgment
Work carried out in the Cowan lab was funded, in part, by DA013429 and T32DA 007237 from the National Institute on Drug Abuse.
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Cowan, A., Kehner, G.B., Inan, S. (2015). Targeting Itch with Ligands Selective for κ Opioid Receptors. In: Cowan, A., Yosipovitch, G. (eds) Pharmacology of Itch. Handbook of Experimental Pharmacology, vol 226. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-44605-8_16
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